Xanthene Food Dye, as a Modulator of Alzheimer's Disease Amyloid-beta Peptide Aggregation and the Associated Impaired Neuronal Cell Function

Abstract

BackgroundAlzheimer's disease (AD) is the most common form of dementia. AD is a degenerative brain disorder that causes problems with memory, thinking and behavior. It has been suggested that aggregation of amyloid-beta peptide (Aβ) is closely linked to the development of AD pathology. In the search for safe, effective modulators, we evaluated the modulating capabilities of erythrosine B (ER), a Food and Drug Administration (FDA)-approved red food dye, on Aβ aggregation and Aβ-associated impaired neuronal cell function.Methodology/Principal FindingsIn order to evaluate the modulating ability of ER on Aβ aggregation, we employed transmission electron microscopy (TEM), thioflavin T (ThT) fluorescence assay, and immunoassays using Aβ-specific antibodies. TEM images and ThT fluorescence of Aβ samples indicate that protofibrils are predominantly generated and persist for at least 3 days. The average length of the ER-induced protofibrils is inversely proportional to the concentration of ER above the stoichiometric concentration of Aβ monomers. Immunoassay results using Aβ-specific antibodies suggest that ER binds to the N-terminus of Aβ and inhibits amyloid fibril formation. In order to evaluate Aβ-associated toxicity we determined the reducing activity of SH-SY5Y neuroblastoma cells treated with Aβ aggregates formed in the absence or in the presence of ER. As the concentration of ER increased above the stoichiometric concentration of Aβ, cellular reducing activity increased and Aβ-associated reducing activity loss was negligible at 500 µM ER.Conclusions/SignificanceOur findings show that ER is a novel modulator of Aβ aggregation and reduces Aβ-associated impaired cell function. Our findings also suggest that xanthene dye can be a new type of small molecule modulator of Aβ aggregation. With demonstrated safety profiles and blood-brain permeability, ER represents a particularly attractive aggregation modulator for amyloidogenic proteins associated with neurodegenerative diseases.

Investigation of the effect of erythrosine B on amyloid beta peptide using molecular modeling

“…Two ERs were employed to investigate the possible inhibition mechanism induced by multiple ERs. In a previous study, various concentrations of ER were investigated based on the molar ratio between ER and Aβ40 monomeric strands; two ERs bound to one Aβ40 [7]. Thus, preparation of two ERs with one Aβ40 in one system is a feasible configuration, even though it may not be common considering the experimental conditions in terms of concentrations.…”

“…Erythrosine B has been implicated as a novel drug candidate to hinder Aβ peptide aggregation [6][7][8]. ER is a common xanthene dye that has been approved by the Food and Drug Administration (FDA).…”

“…ER is a common xanthene dye that has been approved by the Food and Drug Administration (FDA). It is nontoxic to humans at a daily dose of 60 mg/kg and crosses the blood-brain barrier due to its high lipid solubility [7]. Interestingly, this structural characteristic Electronic supplementary material The online version of this article (doi:10.1007/s00894-016-2960-x) contains supplementary material, which is available to authorized users.…”

“…Thus, understanding the inhibition mechanism of ER can be instrumental in the study of other inhibitors as well. Previous studies show that ER binds to the surface of Aβ, which inhibits self-aggregation and dissociates the fibril structure [6,7]. These authors used a dotblotting assay to determine where to bind and its mechanism.…”

Photo-induced inhibition of Alzheimer's β-amyloid aggregation in vitro by rose bengal

“…According to the literature [23e26], halogenation of aromatic molecules significantly affects aromatic interactionmediated self-assembly processes, including Ab aggregation and cytotoxicity. For example, Wong and Kwon reported that erythrosine B, a xanthene dye, can modulate Ab 40 aggregation [27]. Note that competitive interaction between aromatic residues is attributed to the formation of b-sheet rich Аb structures [28].…”